Process for the manufacture of 16beta-methyl desoxycorticosterone and its 21-acetate



United States Patent The present invention relates to a new process formanufacturing 16,8-methyl-desoxycorticosterone 21-acetate of theformula:

Italy, and Emilio Testa,

I sa -QU This compound, which possesses hypertensive activity butsurprisingly, unlike desoxycorticosterone has substantially no effect onelectrolyte metabolism, is also described in our copending applicationSerial No. 239,054, filed simultaneously herewith.

The new process for producing the above mentioned compound consistsessentially in formylating and converting16-methyl-pregna-5,l6-diene-3fi-ol-20-one [A. Wettstein, Helv. Chim.Acta 27, 1803 (1944)] into 16-methylpregna-5,16-diene-3B,21-diol-20-enol acetate and the21-iododerivate, in hydrogenating the A 'double bond with Raney-Nickeland oxidizing the obtained forrnyl ester by known methods to16B-methyldesoxycorticosterone 21- acetate.

The reaction scheme is as follows:

Q Ci?) t or or (\I I I'ICOC\/ J -Cl] (RI-I20 C O CH: C=O

EXAMPLES .1 6-methyl pregna-S ,1 6-die/ze-3/3-0l-20-0ne-3-f0rmale Asolution of 125 g. of 16-methylpregna 5,16-diene-3I3- ol-20-one in 1550ml. of 85% formic acid is heated for 1 hour at C. The solution is pouredinto 15 litres of ice-water, the separated product is collected, Washedto neutrality and dried. 132 g. of a crude product melting at 143-155 C.is recovered and recrystallized from acetone to give 93 g. of16-methylpregna-5,16*diene-3B- ol-20-one-3-formate.

J 6-methylpregna-5 ,1 6,2'0-triene-3fi20-diol-3-f0rmate ZO-acetate Asolution of 45 g. of 1fifi-methylpregnafi,16-diene- 3fi-ol-20-one3-formate in 570 ml. of isopropenyl acetate is heated at the boilingpoint for 12 hours under stirring in the presence of 6 g. ofp-toluene-sulfonic acid.

The isopropenyl acetate mixed with acetone formed during the reaction,is removed on boiling by slow continuous distillation. The distillate ofthe first 6 hours (83 m1.) is replaced by adding to the reactionsolution an equal volume of fresh isopropenyl acetate.

The mixture is cooled to 10 C., diluted with 600 ml. of ethyl ether, theorganic solution is Washed with 250 ml. of a cold 3% sodium bicarbonatesolution and with water to neutrality. The solution is dried over Na SOconcentrated to dryness and the residue taken up with 800 ml. of hexane.The solution is passed through a column containing 80 g. of magnesiumtrisilicate previously washed with fresh hexane.

The eluate is concentrated to a volume of 150 ml., then 15 ml. ofmethanol are added. The resulting white crystalline product is filtered,dried (19 g., MP. 103 113 C.) and recrystallized from methanol, giving14.5 g. of 16-methylpregna-5,16,20-triene-3/3,20-diol-3-formateZO-acetate. Melting point 111116 C.

16-met/zyl-21-i0d0-pregna-5,]6-diene-313-0l-20-0212 3-formale To asuspension of 24 g. of 16-methylpregna-5,16,20-triene-3fi-diol-3-formate ZO-acetate in ml. of dioxane 15.6 g. ofN-iodosuccinimide are added under stirring. The mixture is heated for 45minutes at 80 O15 under a nitrogen stream, then poured into 200 ml. of acold aqueous solution of 10% sodium metabisulfite. A solid productseparates and after a short stirring is collected. Yield: 21 g. of crude2l-iododerivative, melting point 112120 C.

1 6 -mcth ylpregrza-5 ,1 6 dime-5 {3,21 -di0l-200ne 3-formate 21-acetate To a solution of 19 g. of 16-methyl-21-iodo-pregna-5,16-diene-3fi-ol-20-one 3-formate in 240 ml. of acetone 88 ml. ofglacial acetic acid are added, followed after cooling to 1015 C. by m1.of triethylamine. The mixture is refluxed for 45 minutes diluted with2300 ml. of Water and allowed to stand for 1 hour.

Then 20 g. of Celite are added and the solid is collected. The mixtureis washed with water and extracted with acetone. The extracts areconcentrated to a small volume giving 12 g. of a crystalline compoundmelting at 155160 C. From the mother liquors, by concentration andaddition of ether another crop of 2.3 g. or product is obtained. Thecombined crops recrystallized rrom 95% ethanol give 11.4 g. of16-methylpregna-5,16-d1ene-3fl,21- dio1-20-one 3-formate 21-acetate.Melting point 150 162 C.

1 6 fl-methylpregna-S -ene-3B,21 -dil.-200ne-3-f0rmate 21-acetate Asolution obtained by dissolving 8.5 g. ofl6-niethylpregna-S,16-diene-3fl,21-diol-20-one-3 -formate 21-acetate in4000 ml. of hot ethanol is rapidly cooled to 30 C. Then 25 g. ofRaney-Nickel are added and the mixture is hydrogenated under atmosphericpressure at room temperature, filtered and diluted with methanol. Thecatalyst is removed by filtration and the resulting solution isconcentrated under reduced pressure. The dry white solid residue (9 g.melting point 131l35 C.) is re crystallized from isopropyl ether giving6 g. of product melting at l39142 C.

1 6fl-methy lpregna-4-ene-2] -0l-3,20-di0ne-21-acetate (1 6 fl-methyldesoxycorticosterone 21 -acetate) A solution of 6 g. of crude16B-methylpregna-5-ene- 35,21-diol-20-one-3-formate 21-acetate in 240ml. of anhydrous toluene and 96 ml. of cyclohexanone is distilled until40 ml. of toluene .is removed. To the completely anhydrous resultingsolution 6 g. of aluminium isopropoxide dissolved in 48 ml. of anhydroustoluene are added in minutes. The reaction mixture is refluxed understirring for 2 hours, then cooled and washed with a saturated solutionof Seignette salt, then with a diluted NaOH solution and eventually Withwater. The organic phase is dried over Na SO evaporated to dryness andextracted with petroleum ether. After evaporation of the solvent invacuo the oily residue is slurried with ether; 1 g. of16fi-methyldesoxycorticosterone 21-acetate, melting point 133-140 C. canbe separated. The remaining oil is dissolved in benzene and passedthrough a column of A1 0 4 (50 g.); the elution is conducted withbenzene. The first 200 ml. fraction is evaporated and the oily residue(3.2 g.) slurried with petroleum ether. An additional crop of compound,1.05 g., melting point -138 is obtained. Both crops, 2.05 g. arecrystallized from methanol; yield 1.9 g. melting point 142-144" C.

We claim:

1. A process for preparing 16B-methy1-desoxycorticosterone 21-acetate,which comprises heating 16-methylpregna-S,l6-diene-3fl-ol-20-one withaqueous formic acid, refluxing the obtained 3-formyl ester withisopropenyl acetate in the presence of p-toluenesulfonic acid, heatingthe resulting 16-methylpregna-5,16,20-triene-3fi,20-diol 3-formate20-acetate with N-iodosuccinimide, refluxing the crudel6-methyl-21-iodopregna-5,16-diene-3B-ol-20- one 3-formate with aceticacid in the presence of a tertiary aliphatic amine in acetone,hydrogenating the obtained 16-methylpregna 5,16 diene-3fl,21-diol-20-one3- formate Zl-acetate in the presence of a catalyst and subjecting theobtained 16B-methylpregna-5-ene-3fl,2l-diol- 20-one 3-formate 2l-acetateto simultaneous splitting off of the formyl group, oxidation, andshifting of double bond with aluminium isopropoxide in the presence of aketone.

2. A process as in claim 1, wherein hydrogenation of16-methylpregna-5,16-diene-3,B,2l-diol-ZO-one 3-formate 21-acetate iscarried out in the presence of Raney-Nickel.

3. In a process for the preparation of 16fi-methyldesoxycorticosteroneand its acetate, the step which comprises heatingl6-methyl-21-iodopregna-5,16-diene-3fl-ol- 20-one 3-formate with aceticacid in the presence of a tertiary aliphatic amine in acetone to obtainthe corresponding 21-acetate.

References Cited by the Examiner UNITED STATES PATENTS 2,802,839 8/57Ringold et al. 260397.47 2,964,544 12/60 Ringold et al. 260397.47

LEWIS GOTTS, Primary Examiner.

1. A PROCESS FOR PREPARING 16B-METHYL-DESOXYCORTICOSTERONE 21-ACETATE,WHICH COMPRISES HEATING 16-METHYLPREGNA-5, 16-DIENE-3B-OL-20-ONE WITHAQUEOUS FORMIC ACID, REFLUXING THE OBTAINED 3-FORMYL ESTER WITHISOPROPENYL ACETATE IN THE PRESENCE OF P-TOLUENESULFONIC ACID, HEATINGTHE RESULTING 16-METHYLPREGNA-5,16,20-TRIEN-3B,20-DIOL 3-FORMATE20-ACETATE WITH N-IODOSUCCINIMIDE, REFLUXING THE CRUDE16-METHYL-21-IODOPREGNA-5,16-DIENE-3B-OL-20ONE 3-FORMATE WITH ACETICACID IN THE PRESENCE OF A TERTIARY ALIPHATIC AMINE IN ACETONE,HYDROGENATING THE OBTAINED 16-METHYLPREGAN-5,16-DIENE-3B,21-DIOL-20-ONE3FORMATE 21-ACETATE IN THE PRESENCE OF A CATALYST AND SUBJECTING THEOBTAINED 16B-METHYLPREGNA-5-ENE-3B,21-DIOL20-ONE 3-FORMATE 21-ACETATE TOSIMULTANEOUS SPLITTING OFF OF THE FORMYL GROUP, OXIDATION, AND SHIFTINGOF DOUBLE BOND WITH ALUMINUM ISOPROPOXIDE IN THE PRESENCE OF A KETONE.